SP is a peptide consisting of 11 amino acids, and the amino acid sequence thereof is:
(SEQ ID NO: 1)Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2[wherein a carboxyl group of a C-terminal methionine is amidated, and the same applies below].
Meanwhile, HK-1 is a peptide consisting of 11 amino acids and the amino acid sequence thereof is:
(SEQ ID NO: 2)Arg-Ser-Arg-Thr-Arg-Gln-Phe-Tyr-Gly-Leu-Met-NH2.
Both SP and HK-1 belong to the tachykinin peptide family. Here, the term “tachykinin peptide family” refers to a peptide family having FXGLM-NH2 (where X denotes a hydrophobic amino acid) at the C-terminus.
SP is found not only in vertebrates, but also in invertebrates. It is involved in inflammation, pain, itching, muscular contraction, and the like, and it has various functions in an organism. Therefore, the discovery of a novel antagonist against SP is thought to contribute to the development of remedies for suppressing various symptoms in which SP is involved (e.g., pain, inflammation, and itching).
Previous studies have reported that SP is divided into two regions, an N-terminal fragment (SP(1-7): Arg-Pro-Lys-Pro-Gln-Gln-Phe-NH2 (SEQ ID NO: 3)) and a C-terminal fragment (SP(7-11): Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO: 4)), wherein these fragments have different functions (Non-patent Document 1). Specifically, SP administered to a rat or a mouse induces pain-related behavior (e.g., scratching behavior). However, pain-related behavior can be suppressed by administration of the N-terminal fragment of SP. On the other hand, pain-related behavior is induced by administration of the C-terminal fragment of SP.
It has also been reported that the N-terminal fragment (SP(1-7): Arg-Pro-Lys-Pro-Gln-Gln-Phe-NH2 (SEQ ID NO: 3)) of SP and the N-terminal fragment (SP(1-8): Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-NH2 (SEQ ID NO: 5)) of SP suppress pain-related behavior resulting from SP (Non-patent Documents 2 and 3).
HK-1 is a peptide suggested to be present based on human and rodent TAC4 genes. However, it remains unknown if an HK-1-specific receptor differs from a receptor (neurokinin-1 receptor (NK1R)) for SP belonging to the same family of HK-1.
There is a view suggesting that an HK-1 specific receptor is NK1R based on the facts that: HK-1 has high affinity for NK1R in a manner similar to that of SP (Non-patent Documents 4, 5, and 6); intrathecal administration of HK-1 and SP to rats induces scratching behavior in a manner depending on the concentrations of peptides administered (Non-patent Document 7); and the behavior is also suppressed by known NK1R antagonists (L-703,606) (Non-patent Documents 7 and 8).
However, it is known that (1) intrathecal administration of SP induces thermal hyperalgesia (Non-patent Documents 9 and 10), but HK-1 administration results in no such reaction at all (Non-patent Documents 7 and 11), (2) pre-administration of endokinin C/D (EK C/D) composed of a consensus amino acid sequence corresponding to 12 amino acids from the C-terminal region of endokinin C and endokinin D, which are endokinin peptides belonging to the tachykinin peptide family, can suppress SP-induced scratching behavior, but cannot suppress HK-1-induced scratching behavior (Non-patent Document 8), and (3) evaluation (performed using as an indicator the inhibition of receptor desensitization resulting from treatment of the intracellular signal transduction pathway involved in receptor desensitization using various protein kinase inhibitors) suggests the involvement of different protein kinases in receptor desensitization induced by SP and HK-1 (Non-patent Document 12). Based on these results, it is assumed that receptors (HK-1-preferred receptors) specific to HK-1, which differ from NK1R, are present and the receptor functions thereof are analogous to each other, but are not the same (Non-patent Documents 7, 8, and 13).